SETDB1
Description
The SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a protein-coding gene located on chromosome 1.
Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the SETDB1 gene. SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET. The SET domain is a highly conserved motif involved in chromatin structure modulation. It was originally identified in Drosophila and has been implicated in regulating transcriptionally active or repressed chromatin states. SETDB1 interacts with TRIM28. SETDB1 is highly homologous to SETD1A.
SETDB1 is a histone methyltransferase that specifically adds three methyl groups (trimethylates) to lysine 9 of histone H3. This modification, H3K9me3, acts as a marker for epigenetic transcriptional repression, attracting HP1 proteins (CBX1, CBX3, and/or CBX5) to the methylated histones. SETDB1 primarily functions in euchromatin regions, contributing significantly to the silencing of euchromatic genes. H3K9me3 is coordinated with DNA methylation. SETDB1 is essential for HUSH-mediated heterochromatin formation and gene silencing. It forms a complex with MBD1 and ATF7IP, repressing transcription and linking DNA methylation with H3K9me3. Its activity is dependent on MBD1 and is inherited through DNA replication due to recruitment by CAF-1. TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins, targets SETDB1 to histone H3. SETDB1 likely forms a corepressor complex involved in activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells. It is required to maintain the transcriptionally repressed state of genes in undifferentiated embryonic stem cells (ESCs). In ESCs, collaborating with TRIM28, SETDB1 is also needed for H3K9me3 and the silencing of endogenous and introduced retroviruses via a DNA-methylation-independent pathway. SETDB1 associates with promoter regions of tumor suppressor genes (TSGs), leading to their silencing. The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc-finger coding genes with atypical chromatin signatures, establishing or maintaining/protecting H3K9me3 at these transcriptionally active regions.
SETDB1 is also known as ESET, H3-K9-HMTase4, KG1T, KMT1E, TDRD21.
